1. Field of the Invention
This invention relates to the field of biochemistry, and provides a method of treating mammary cancer with certain antiestrogenic agents.
Estrogen is transported by the bloodstream and passively enters cells. However, only certain tissues exhibit responses to the hormone and are accordingly called estrogen target tissues. These target tissues are characterized by the presence of specific estrogen receptors. The interaction of the estrogen with estrogen receptors in the cytoplasm of target cells is an early event in a complex series of events which result in an estrogenic response. The uterus, vagina and breast are considered the primary target tissue for estrogen. They are rich in estrogen receptors and exhibit dramatic growth under the influence of estradiol. The uterotropic response of laboratory animals is a convenient, reproducible model for the evaluation of antiestrogenic and estrogenic activity, as well as for the study of interactions with estrogen receptors.
A relationship has been established between estrogen sensitivity or dependency, and the occurrence of estrogen receptors in mammary cancers. The neutralization of estrogen influence on those tissues is expected to benefit patients with such a cancer by inhibiting the growth of it, and even by causing the regression of the cancer or by preventing recurrence of it.
Antiestrogens antagonize the action of estrogens, such as estradiol, in animals and display clinical efficacy in about half of the mammary cancers which contain estrogen receptors. They interact with estrogen receptors, and elicit partial estrogenic responses. Their estrogenic response is measured and described by their partial agonist (uterotropic) properties. Known antiestrogens display, in widely varying degrees, some agonist characteristics: that is, the administration of one of them to a normal animal produces some uterotropic response, as though a weak estrogen had been administered; this effect is termed the agonist effect. Such compounds also exhibit an estrogen antagonist effect: that is, administration of one of them to an estrogen-treated animal will cause a reduction in the uterotropic response caused by the estrogen.
It has long been known that estrogen target tissues have many receptor sites which specifically bind estradiol. It has more recently been proposed that such tissues also contain another receptor site, which does not appear to bind estradiol, but which does bind some known antiestrogens. See Faye et al., Biochem. and Biophys. Res. Comm. 93, 1225-31 (1980), and Sutherland et al., Nature 288, 273-75 (1980).
This invention makes use of a combination of two antiestrogens which have quite different partial agonist/antagonist properties.
2. State of the Art
At least one drug is now sold as an antiestrogen for palliative cancer therapy; it is tamoxifen, 1-(4-.beta.-dimethylaminoethoxyphenyl)-1,2-diphenylbut-1-ene, British Pat. No. 1,013,907.
Antiestrogens which have been clinically tested in cases of advanced mammary cancer include trioxifene mesylate, 2-[4-(2-pyrrolidinoethoxy)benzoyl]-1-(4-methoxyphenyl)-3,4-dihydronaphthal ene, methanesulfonic acid salt, which is described in U.S. Pat. No. 4,230,862, of Suarez and Jones, clomiphene, 2-[4-(2-chloro-1,2-diphenylvinyl)phenoxy]triethylamine, U.S. Pat. No. 2,914,563, of Allen et al., and nafoxidine, 6-methoxy-2-phenyl-1-[4-(2-pyrrolidinoethoxy)phenyl]-3,4-dihydronaphthalen e.
The benzothiophenes of Jones and Suarez, U.S. Pat. No. 4,133,814, are also known antiestrogens. Tests of one of their compounds, 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-pyrrolidinoethoxy)benzoyl]benzo[b]-t hiophene, LY117018, have been published by Black and Goode, Life Sciences 26, 1453-58 (1980). The same article also discussed similar tests of tamoxifen and trioxifene, giving their partial agonist/antagonist properties.
Another pertinent document on antiestrogens is U.S. patent application Ser. No. 246,335 of Jones, which teaches 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thi ophene and some derivatives thereof, which compound is described as a particularly effective antiestrogen.